Analysis Of Risk Factors Of Liver Failure Caused By Anti Tuberculosis Drugs And Serum Interleukin 10,18,22 And IP10 Levels In Patients With Drug-induced Liver Injury

Data released by the WHO 2016 report shows that in 2015 there were 1040 million new TB worldwide,of which 1 million 400 thousand people died of tuberculosis,while China’s new TB patients were 918 thousand,ranking the world’s third.In the process of anti tuberculosis treatment in the current adverse reactions,the most serious is the highest frequency of drug-induced liver injury(Drug induced liver injury,DILI,DILI)which will interrupt the regular anti tuberculosis treatment,increase the incidence of drug-resistant tuberculosis,severe cases may progress to liver failure,cause the death of the patient.China is a big country with hepatitis B virus,the national HBsAg positive is about about 90 millions,the number of patients with hepatitis B is not a minority.In our clinical treatment,it can be observed that these patients often have more severe liver injury after DILI,and the prognosis is worse.At present,the study of DILI is mainly to explore the risk factors of DILI in patients taking anti tuberculosis drugs therapy,but there is less research on the progression of DILI to liver failure and its prognosis.Therefore,this study was to explore the risk factors of progression to liver failure and its prognosis after DILI administration.To provide guidance for clinical and detection of some cytokines in patients with anti tuberculosis drug-induced liver injury(ATDILI),analyze the effect of HBV infection on the level of inflammation in patients with DILI.ObjectiveTo investigate the risk factors for the occurrence and prognosis of liver failure induced by anti-tuberculosis drugs.The levels of IL-10,IL-18,IL-22 and IP10 in serum of patients with ATDILI were detected.To investigate the effect of HBV infection on the level of inflammation in patients with DILI,and to provide a new direction for clinical treatment.MethodPart 1: The clinical data of 343 patients with drug-induced liver injury caused by anti-tuberculosis drugs,who were hospitalized in our hospital between January 2012 and June 2016,were retrospectively analyzed.Univariate and multivariate Logistic regression analysis of risk factors for the occurrence and prognosis of patients with drug induced liver failure(DILF),and draw ROC curve.Based on the results of Logistic regression,the prognosis model of patients with liver failure was established,and determine the optimal critical value.Select the factors of DILF were gender,age,BMI,anti tuberculosis treatment protocol,chronic HBV carrier,HBV-DNA,hepatitis C,hepatitis E,liver cirrhosis,diabetes,hypertension,fatty liver,alcohol history,classification of DILI.Select the factors of DILF prognosis were gender,age,BMI,anti tuberculosis treatment protocol,chronic HBV carrier,HBV-DNA,hepatitis E,liver cirrhosis,diabetes,hypertension,alcohol history,artificial liver treatment,classification of DILI,TBIL,ALB,PTA,AFP,TC,ascites,hepatic encephalopathy,hepatorenal syndrome and mycotic infection.Part 2: 53 patients with DILI during anti tuberculosis treatment were selected from the inpatients in our hospital.There were 30 patients with HBsAg negative and 23 patients with HBsAg positive.A total of 17 patients(17/53)were followed up for 4 weeks.And 28 patients with CHB were selected from outpatients and inpatients.27 patients were selected as control group who had been treated with anti tuberculosis for more than 2 months and regularly reviewed for normal liver function.20 healthy persons were selected as healthy control group.The serum of each group were collected.The levels of IL-10,IL-18,IL-22 and IP10 in peripheral blood of patients in each group were detected by ELISA.Detection of laboratory indicators and the prognosis of DILI patients were statistically analyzed.Result Part 1: 1.The incidence of ATDILI was higher in males than in females in our hospital.The incubation period is more than 2 months.Yellow urine,anorexia,fatigue,jaundice is the main clinical manifestation.2.Univariate Logistic regression analysis showed that age,chronic HBV carrier,hepatitis E,liver cirrhosis and alcohol history were risk factors for liver failure in patients with DILI.Multivariate Logistic regression analysis was used to screen out the age,chronic HBV carrier,hepatitis E,liver cirrhosis.3.Univariate Logistic regression analysis showed that age,chronic HBV carrying,alcohol history,artificial liver therapy,PTA,ascites and hepatic encephalopathy were risk factors for ATDILF treatment.Multivariate Logistic regression analysis was used to screen the three factors of chronic HBV carrying,age and PTA for the regression model of liver failure.The regression model: P(Y=1,X)=1/1+e-logit P,Logit P =-2.794+1.608X2 +1.472X5+1.333X18,X2,X5 and X18 which were age,chronic HBV carriers,PTA,P for the treatment of patients with liver failure probability.The area under the ROC curve was 0.821,and the 95% confidence interval(0.736,0.906).The clinical data of 30 patients with ATDILF were enrolled in the model,and the reliability of the model was verified to be 76.7%.Part 2: 1.The IL-10,IL-18,IL-22 and IP10 in serum of HBsAg positive DILI group and HBsAg negative DILI group were significantly higher than those in the TB control group and the healthy control group,the difference was statistically significant(P<0.05).After 4 weeks of treatment,serum IL-10,IL-18,IP10 in patients with DILI were significantly lower than baseline,the difference was statistically significant(P<0.05).The serum IL-22 level of patients with DILI was higher than baseline at 4 weeks,the difference was statistically significant(P<0.05).2.The expression levels of IL-10,IL-18 and IP10 in serum were higher in HBsAg positive DILI patients than in HBsAg negative DILI patients,but there was no significant difference(P>0.05).The expression level of IL-22 in serum was higher in HBsAg negative DILI patients than in HBsAg positive DILI patients,the difference was statistically significant(P<0.05).The level of ALT in HBsAg positive DILI patients was higher than that in HBsAg negative DILI patients,the difference was statistically significant(P<0.05).3.When ALT is larger than 5ULN,the serum of patients with DILI in IL-10,IL-18,IL-22,IP10 were significantly increased,the difference was statistically significant(P<0.05).4.The serum IL-22 level of the patients with DILI in the rehabilitation group was significantly higher than that in the control group at 4 weeks,the difference was statistically significant(P<0.05).5.The expression level of IL-18 in serum of patients with DILI was positively correlated with ALT,AST,TBIL(P<0.05),and the expression level of IP10 in serum of patients with DILI was positively related to ALT,AST and TBIL(P<0.05).Conclusion 1.Patients older,chronic HBV carriers,and patients with hepatitis E and liver cirrhosis are more likely to develop liver failure after drug induced liver injury during anti tuberculosis treatment,and the prognosis of liver failure in patients older,chronic HBV carriers and patients with lower PTA may be poor.2.IL-10,IL-18,IL-22 and IP10 are involved in the pathogenesis of DILI and the expression levels of IL-10,IL-18,IL-22 and IP10 were related to the severity of liver inflammation.3.Elevated IL-18 and IP10 in serum of HBsAg positive DILI patients may lead to more severe liver injury,and lower serum IL-22 may lead to worse prognosis.4.The serum IL-22 in patients with DILI is related to the prognosis of the patients.It is expected to be a new index for prognosis of patients with DILI.And may become a new direction in the treatment of patients with DILI.